Antiestrogens are used widely in the treatment of breast cancer and are thought to function as anticancer drugs primarily by inhibiting estradiol-stimulated tumor growth. We have recently observed that quinone reductase (QR) activity is increased in breast cancer cells by antiestrogens via an estrogen receptor (ER)-dependent mechanism. The increase in QR by antiestrogen may provide protective effects against the toxicity and mutagenicity caused by quinones, and contribute to the beneficial antioxidant and anticancer activities of antiestrogens. Since QR can also metabolize and activate chemotherapeutic quinones, antiestrogens may increase the effectiveness of chemotherapeutic agents that are activated by QR. I therefore propose to test the following hypothesis: ER-dependent pathways for antiestrogens and the ER- independent pathway for electrophiles may merge in a common mechanism at the level of nuclear protein binding to the electrophile/antioxidant response elements (EpRE/AREs) leading to the activation of QR and possibly other EpRE-containing genes. We further propose that antiestrogen-mediated stimulation of QR will potentiate the responsiveness of breast cancer cells to chemotherapeutic agents that are activated by QR. The specific aims of this proposal are to: (1) determine the mechanism of antiestrogen-mediated activation of QR; (2) determine if antiestrogens can activate other detoxifying enzymes and other proteins that are known to be transcriptionally regulated through EpREs; and (3) determine if antiestrogens increase the sensitivity of breast cancer cells to bioreductive chemotherapeutic agents that are activated by QR. It is anticipated that these studies will provide new insight as to how antiestrogens function as anticancer agents and increase our understanding of the regulation of detoxifying enzymes and other proteins whose transcription is under the control of EpRE/AREs.